This invention relates to closed loop drug delivery systems and more specifically to systems for controlling the infusion rate of insulin based on continuously monitored body glucose levels.
The pancreas of a normal healthy person produces and releases insulin into the blood stream in response to elevated blood plasma glucose levels. Bata cells (xcex2-cells), which reside in the pancreas, produce and secrete the insulin into the blood stream, as it is needed. If xcex2-cells become incapacitated or die, a condition known as Type I diabetes mellitus (or in some cases if xcex2-cells produce insufficient quantities of insulin, Type II diabetes), then insulin must be provided to the body from another source.
Traditionally, since insulin cannot be taken orally, insulin has been injected with a syringe. More recently, use of infusion pump therapy has been increasing, especially for delivering insulin for diabetics. For example, external infusion pumps are worn on a belt, in a pocket, or the like, and deliver insulin into the body via an infusion tube with a percutaneous needle or a cannula placed in the subcutaneous tissue. As of 1995, less than 5% of Type I diabetics in the United States were using infusion pump therapy. Presently over 7% of the more than 900,000 Type I diabetics in the U.S. are using infusion pump therapy. And the percentage of Type I diabetics that use an infusion pump is growing at an absolute rate of over 2% each year. Moreover, the number of Type I diabetics is growing at 3% or more per year. In addition, growing numbers of insulin using Type II diabetics are also using infusion pumps. Physicians have recognized that continuous infusion provides greater control of a diabetic""s condition, and are also increasingly prescribing it for patients. Although offering control, pump therapy can suffer from several complications that make use of traditional external infusion pumps less desirable for the user.
According to an embodiment of the invention, a closed loop infusion system is for controlling blood glucose concentration in the body of a user. Embodiments of the present invention include a sensor system that measures a glucose level in the body of the user, a controller that uses the measured glucose level to generate commands, and an insulin infusion system that infuses insulin into the body of the user in response to the commands.
According to another embodiment of the invention, a closed loop infusion system is for infusing a fluid into a user. The closed loop infusion system includes a sensor system, a controller, and a delivery system. The sensor system includes a sensor for monitoring a condition of the user. The sensor produces a sensor signal, which is representative of the condition of the user, and is used to generate a controller input. The controller uses the controller input to generate commands that affect the operation of the delivery system. Accordingly, the delivery system infuses a liquid into the user. In particular embodiments, glucose concentration is monitored by the sensor system, and the liquid delivered to the user includes insulin. In preferred embodiments, the sensor system sends a message, generated using the sensor signal, to the delivery system. The message is used to generate the controller input. In particular embodiments, the sensor is a subcutaneous sensor in contact with interstitial fluid. In further particular embodiments, two or more sensors are included in the sensor system.
In preferred embodiments, the sensor system is predominately external to the user""s body. And the delivery system is predominately external to the user""s body. In alternative embodiments, the sensor system is predominately internal to the user""s body. In other alternative embodiments, the delivery system is predominately internal to the user""s body.
In preferred embodiments, the sensor signal is used to generate digital sensor values, and the digital sensor values are processed through at least one of a group of components that includes one or more pre-filters, one or more filters, one or more calibrators and one or more post-calibration filters to generate the controller input. In particular embodiments, the one or more pre-filters uses a group of digital sensor values, calculates a parameter using at least a subset of the group of digital sensor values, establishes one or more thresholds relative to the parameter, compares each digital sensor value within the group to the one or more thresholds, and changes the value of any digital sensor value that is outside of the one or more thresholds. In further particular embodiments, the one or more pre-filters compares the digital sensor values to one or more thresholds, and a flag is set when one or more digital sensor values are outside of at least one threshold.
In preferred embodiments, the digital sensor values are processed through at least one FIR filter, preferably at least a 7th order FIR filter. In addition, a preferred FIR filter has a pass band for frequencies from zero up to between about 2 cycles/hour and 5 cycles/hour and a stop band beginning at 1.2 to three times the selected pass band frequency. In particular embodiments, the FIR filter has a pass band for frequencies from zero up to between about 2 cycles/hour and 10 cycles/hour and a stop band beginning at 1.2 to three times the selected pass band frequency. In other particular embodiments, the FIR filter has a pass band for frequencies from zero up to less than or equal to 10 cycles/hour. Preferred embodiments include a FIR filter that compensates for time delays of between zero and 30 minutes. In particular embodiments, the FIR filter compensates for time delays of between 3 and 10 minutes.
In preferred embodiments, the controller uses a first set of one or more controller gains when the glucose concentration is higher than a desired basal glucose concentration and the controller uses a second set of one or more controller gains when the glucose concentration is lower than a desired basal glucose concentration. In alternative embodiments, the controller uses a first set of one or more controller gains when the glucose concentration is increasing and a second set of one or more controller gains when the glucose concentration is decreasing. In further alternative embodiments, the controller uses a first set of one or more controller gains when the glucose concentration is higher than a desired basal glucose concentration and the glucose concentration is increasing; and the controller uses a second set of one or more controller gains when the glucose concentration is higher than a desired basal glucose concentration and the glucose concentration is decreasing; and the controller uses a third set of one or more controller gains when the glucose concentration is lower than a desired basal glucose concentration and the glucose concentration is increasing; and the controller uses a fourth set of one or more controller gains when the glucose concentration is lower than a desired basal glucose concentration and the glucose concentration is decreasing.
In preferred embodiments, one or more controller gains are selected such that the commands generated by the controller cause the delivery system to infuse insulin into the body of the user in response to a glucose concentration at a rate similar to the rate that beta cells would release insulin in an individual with a healthy normally functioning pancreas. Alternatively, one or more controller gains are selected so that the commands generated by the controller cause the delivery system to infuse insulin into the body of the user in response to a glucose concentration at a rate such that the insulin concentration profile in the user""s blood stream is similar to the insulin concentration profile that would be generated by the release of insulin beta cells in an individual with a healthy normally functioning pancreas. In other alternative embodiments, a post-controller lead/lag compensator is used to modify the commands generated by the controller to cause the delivery system to infuse insulin into the body of the user in response to a glucose concentration at a rate such that the insulin concentration profile in the user""s blood stream is similar to the insulin concentration profile that would be generated by the release of insulin beta cells in an individual with a healthy normally functioning pancreas.
In preferred embodiments, one or more controller gains are selected by a method that includes the step of measuring an insulin response of at least one individual with a healthy normally functioning pancreas and calculating the controller gains that cause the commands to generally match the insulin response of at least one individual. In particular embodiments, the derivative gain KD is calculated using the first phase insulin response (xcfx861) measured from a normal glucose tolerant (NGT) individual. In further particular embodiments, one or more controller gains are calculated from a ratio of one or more controller gains.
In preferred embodiments, a post-controller lead/lag compensator is used to modify the commands generated by the controller to compensate for an insulin delivery delay due to infusing insulin into a user"" tissue rather than directly into the user""s blood stream.
In alternative embodiments, the controller is influenced by inputs of more than one measured body characteristic. For example, measured body characteristics that might be used to influence the controller include one or more amino acid concentrations, one or more gastrointestinal hormone concentrations, one or more other hormone concentrations, blood pH, interstitial fluid (ISF) pH, one or more blood glucose concentrations, and one or more interstitial fluid (ISF) glucose concentrations. In particular embodiments, the sensor is a multi-sensor that measures both glucose concentration and pH.
In preferred embodiments, the sensor system produces a diagnostic signal in addition to the sensor signal, and the diagnostic signal is used to indicate when the sensor signal accuracy has diminished.
According to an embodiment of the invention, a closed loop infusion system is for infusing a fluid into a user. Embodiments of the invention include a sensor system, a proportional plus, integral plus, derivative (PID) controller, and a delivery system. The sensor system includes a sensor for monitoring glucose concentration of the user. The sensor system produces a sensor signal, which is representative of the glucose concentration of the user, and the sensor signal is used to generate a controller input. The controller uses the controller input to generate commands. The delivery system infuses a liquid, which includes insulin, into the user, and the operation of the delivery system is affected by the commands. In particular embodiments, the controller is influenced by one or more manual inputs from the user. The manual inputs from the user may include one or more of the start of a meal, the number of carbohydrates in a meal, the beginning of exercise for the body of the user, the duration of the exercise for the body of the user, the start of sleep for the user, and the duration of sleep for the user.